Recent evidence suggests that tissue concentrations of glucocorticoids, such as cortisol, can be controlled independently of circulating glucocorticoid concentrations. Walker et al., Ann. N.Y. Acad. Sci. 1083:165-184 (2006). This control may be attributed to local intracellular expression of 11βHSD1. 11βHSD1 is a microsomal enzyme that catalyzes the conversion of cortisone to cortisol. Cortisol has a wide range of physiological effects including; regulation of carbohydrate, protein and lipid metabolism, regulation of normal growth and development, influence on cognitive function, resistance to stress and mineralocorticoid activity. Cortisol stimulates hepatic gluconeogenesis and inhibits peripheral glucose uptake, the net effect of which is an increase in blood glucose concentration. Glucocorticoids are also essential in the regulation of the immune response. When circulating at higher concentrations, glucocorticoids are immunosuppressive and are used pharmacologically as anti-inflammatory agents.
There are two isoforms of 11βHSD: 11βHSD1 and 11βHSD2. Recent evidence suggests that disregulation of 11βHSD1 may lead to conditions typically associated with the metabolic syndrome, whereas the absence of 11βHSD2 is often associated with hypertension (Walker et al., supra.).
11βHSD1 is highly expressed in liver. It is also expressed at lower, buy physiologically relevant levels in adipose tissue, lung, and areas of the central nervous system. The primary in vivo function of 11βHSD1 is to convert cortisone to cortisol. (Walker et al., supra) As such, the literature suggests that the physiological role of 11βHSD1 is to maintain activation of the glucocorticoid receptor where required for proper metabolic activity. This may be particularly relevant during the trough phase of the diurnal rhythm of adrenal cortisol production. In cases where 11βHSD1 expression is inappropriately elevated, the increased cortisol levels in adipose tissue and liver would promote development of symptoms associated with metabolic diseases such as obesity, hyperglycemia, hyperlipidemia and hypertension. Inhibition of 11βHSD1 under these circumstances may provide a means to reduce cortisol levels and, as a result, abolish conditions associated with the metabolic disease. Thus, identification of compounds that modulate 11βHSD1 activity would be useful for developing treatments for diseases such as diabetes and obesity.
One of the challenges faced by those discovering and developing inhibitors of 11βHSD1 for clinical use is species specificity. It is often the case that inhibitors that are potent versus the human enzyme are significantly less potent against the enzyme in commonly used animal models. This significantly hampers the use of these animal models to judge the in vivo potency and efficacy of lead molecules, thereby making predictions of doses in clinical trials extremely difficult. For example, despite the approximately 80% homology at the amino acid level between human and mouse 11βHSD1, compounds that are very potent inhibitors of human 11βHSD1 are often found to be weakly potent inhibitors of mouse 11βHSD1. For instance, a bicyclic triazolopyridyl (TZP) compound designated “Compound A” has an IC50 of 4 nM for human 11βHSD1. Yet the IC50 for Compound A is 625 nM against mouse 11βHSD1—a 160 fold difference. This low potency versus the mouse enzyme would, for all practical purposes, preclude testing in mice.
Since most animal models of metabolic disease are murine based, the efficacy of a compound with a desirable in vitro potency profile versus the human enzyme cannot be confirmed in vivo prior to initiation of clinical trials. This leads to three potential issues for a drug discovery and developmental organization. First, compounds sometimes possess unanticipated benefits that can only be observed upon in vivo efficacy testing. Without an appropriate in vivo test, an otherwise desirable profile may be unintentionally discarded. Second, compounds that seem potent against the human enzyme in vitro may not perform well in vivo for unanticipated reasons. This leaves open the possibility that an undesirable compound may be progressed unnecessarily. Third, it severely confounds the estimation of efficacious human doses for clinical study. Thus, there remains a need for a reliable 11βHSD1 mouse model for screening compounds which modulate 11βHSD1 activity.